There is a critical need for safe, inexpensive treatments that can delay the progression of cyst enlargement and the accompanying destruction of the renal parenchyma that leads to renal failure in the majority of autosomal polycystic kidney disease (ADPKD) patients. In ADPKD, the earlier the onset of treatment, the greater the potential benefit to the patient, therefore, drugs for this disease should be considered life-long therapy. Our overall goal is to develop efficacious drugs that can be safely used from the time of diagnosis in ADPKD patients. The objective in the proposed studies is to conduct a preliminary evaluation of drug therapy using a low dose of an insulin sensitizing agent, the PPAR? agonist, pioglitazone, in the treatment of ADPKD. Our previous cell culture studies showed that low doses of PPAR? agonists, including pioglitazone, inhibit the synthesis of the CFTR (cystic fibrosis transmembrane conductance regulator) Cl- channel in the cell type that lines the renal cysts. CFTR is the major ion channel postulated to be involved in transepithelial Cl- and, secondarily, water flux into the cyst lumen resulting in cyst expansion. Our in vivo animal studies have shown that the two FDA approved PPAR? agonists, pioglitazone or rosiglitazone, inhibited cyst growth in the PCK rat model of PKD. In addition to inhibiting cyst growth, PPAR? agonist therapy is expected to have beneficial effects on other parameters of PKD such as dyslipidemia, hypertension and endothelial function. Based on these data, we hypothesize that treatment with low dose pioglitazone will slow cyst expansion in human ADPKD patients and delay the progression of disease. The proposed study is a double-blind, placebo controlled, cross-over trial of pioglitazone (15 mg/day) versus placebo therapy for the treatment of ADPKD. The study is a pilot study to test the safety and efficacy of pioglitazone to slow progression of PKD assessed by percent change in kidney volume by MRI compared to one year of placebo. 28 subjects will be enrolled. A one year cross-over design provides the best opportunity to obtain meaningful safety and efficacy data in a short term protocol by allowing each patient to serve as his/her own control. This will facilitate the design of a future multi center randomized trial. Based on data from large scale studies in normal volunteers and diabetic patients, low dose pioglitazone is relatively safe for long term treatment. Thus, this drug may provide a safe option for treatment of ADPKD patients and an increase in length and quality of life.